Design and synthesis of cyclic depsipeptides containing triazole (CDPT) rings

Article abstract of DOI:10.1039/c3ra45100c

We report the synthesis of cyclic depsipeptides containing triazole (CDPT) rings using click chemistry. 1,3-Dipolar cyclization via Cu^I- catalyzed alkyne-azide coupling gave the CDPT ring in a 58-64% yield.

Full text of DOI:10.1039/c3ra45100c

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Design and synthesis of cyclic depsipeptides
containing triazole (CDPT) rings†
Cite this: RSC Adv., 2014, 4, 10728
a
b
a
Sumit K. Agrawal, Piyush Panini, Manisha Sathe, Deepak Choprab
*
and M. P. Kaushika
Received 13th September 2013
Accepted 20th December 2013
DOI: 10.1039/c3ra45100c
www.rsc.org/advances
We report the synthesis of cyclic depsipeptides containing triazole membrane permeability and bioavailability in vivo.7 Maarseveen
(CDPT) rings using click chemistry. 1,3-Dipolar cyclization via CuI- et al. incorporated triazole rings in place of an amide linkage to
catalyzed alkyne–azide coupling gave the CDPT ring in a 58–64% synthesise the triazole analogue (2) of a naturally occurring
yield.
cyclic peptide (1) which is a potent tyrosinase inhibitor.8 On the
other hand, sansalvamide A is a natural cyclic depsipeptide (3)
which has in vitro cytotoxicity towards COLO 205 colon and SK-
MEL-2 melanoma cancer cell lines.9 A number of amide deriv-
atives (4) (ref. 10) and macrocyclic analogues of sansalvamide A
(ref. 11) have been synthesized and evaluated against various
cancerous cell lines, many of which have been found to be more
potent than the natural compound (Fig. 1).
To demonstrate the cyclization potential of click chemistry
on peptides as part of our ongoing program of synthesising a
new class of bioactive molecules,12 we have designed and
synthesized a series of cyclic depsipeptides containing triazole
(CDPT) rings. The CDPT ring (10) was designed as a hybrid of 2
and 3 with a bicyclic/14-membered ring structure. We proposed
a pathway to synthesise the CDPT ring analogue 10 (Scheme 1),
Cyclic peptides are a large and diverse class of natural products
which can contain both proteinogenic and nonproteinogenic
amino acids, and whose equally diverse range of biological
activities makes them and their analogues important targets for
organic synthesis.1 Considering the vast application of cyclic
peptides and their analogues in synthetic as well as in medic-
inal chemistry, cyclic peptides remain an important area of
study for both academic and industrial laboratories. Head-to-
tail or cyclization via peptide bond formation poses signicant
challenges, such as oligomerization (a possible side reaction),
and ring strain in the transition state which can prohibit
cyclization altogether.2 Despite this, cyclic peptides containing
triazole have been developed. This method involves the use of a
1,4-disubstituted-1,2,3-triazole as an amide bond surrogate and
cyclization aid. These triazoles have atom placement and elec-
tronic properties similar to those of a peptide bond,3 and are
accessible in one step via CuI-catalyzed alkyne–azide cycload-
dition.4 Furthermore, the increased ring size of the triazole
analogue and the apparent “ring contraction” mechanism of
CuI-catalyzed alkyne–azide cycloaddition5 may help to promote
cyclization.6 The literature also reveals that the incorporation of
other functional groups into the cyclic peptide enhances the
aDiscovery Centre, Defence R & D Establishment, Jhansi Road, Gwalior, M.P., India.
E-mail: drmanishasathe@drde.drdo.in
bDepartment of Chemistry, IISER Bhopal, Bhauri, Bhopal 462030, M.P., India
† Electronic supplementary information (ESI) available. CCDC 957560. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ra45100c
‡ Crystal data of 10e: C17H27N5O4; M ¼ 365.44 g molꢀ1, orthorhombic, P212121,
˚
colourless, thin plate 0.16 ꢁ 0.10 ꢁ 0.05 mm, T ¼ 150(2) K, a ¼ 9.359(4) A,
3
b ¼ 10.657(4) A, c ¼ 19.105(7) A, V ¼ 1905.4(13) A , r ¼ 1.274 g cmꢀ3, Z ¼ 4, m ¼
0.092 mmꢀ1, no. unique/observed reections ¼ 3104/1664, no. of parameters ¼
˚
˚
˚
240, R1 ¼ 0.0719, wR2 ¼ 0.1679, GoF ¼ 0.906, Drmin/max(e Aꢀ3) ¼ ꢀ0.231/0.262.
Fig. 1 Structure of natural and synthesized cyclic peptides.
˚
10728 | RSC Adv., 2014, 4, 10728–10730
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Table 1 Synthesis of cyclic depsipeptides containing triazole (CDPT)
rings
Yielda (%)
Entry
R1
R2
6
7
9
10
a
b
c
d
e
f
g
h
i
Leu
Val
Ile
Val
Ile
Val
Val
Val
Val
Ile
Phe
Ile
Phe
Phe
Val
Leu
Val
Gly
68
72
67
74
62
75
72
68
65
69
70
70
75
65
76
67
69
76
73
65
68
72
70
73
69
72
65
72
70
68
74
72
70
62
58
60
64
61
59
62
59
58
64
62
Scheme 1 Retrosynthetic analysis of the CDPT ring.
Ala
Tyr
Ser(OBz)
j
k
disconnecting the lone triazole ring retrosynthetically to give a
linear azido–alkyne depsipeptide 9, because the literature
suggests that the cyclization of triazole analogues of a cyclic
peptide via click chemistry is feasible through cyclization via
peptide bond formation.6e,8 The linear depsipeptide (9) was
disconnected further to the propargyl ester containing dipep-
tide 7, and 3-azido propionic acid 8.13 7 was nally disconnected
to Boc protected amino acid 5 and propargyl amino ester 6.
We set out initially to synthesize CDPT 10a, in order to
evaluate the viability of the proposed route and its efficiency
relative to the cyclization method (Scheme 2, see ESI†).
Synthesis of 6a was achieved via 1,10-carbonyl diimidazole (CDI)
mediated esterication of Boc–Leu–OH (5a) with propargyl
alcohol, followed by triuoroacetic acid (TFA) removal of the
Boc group in quantitative yield. Boc–Phe–OH (5b) was then
coupled with 6a to give the Boc protected propargyl ester con-
taining dipeptide, which on treatment with TFA gave the TFA
salt of propargyl ester containing dipeptide 7a. EDC$HCl/HOBt
mediated peptide coupling of 3-azido propionic acid13 with 7a
gave the linear azido–alkyne depsipeptide 9a cleanly in 70%
yield. Addition of copper(I) bromide to a reuxing solution of 9a
in toluene and DBU led to the formation of the desired cyclic
depsipeptide containing triazole ring 10a in 62% yield. With the
optimized reaction conditions in hand, the scope of the meth-
odology was explored for the synthesis of a library of CDPT rings
and is given in Table 1.
Ile
a
Isolated yield for each step.
As shown in Table 1 the desired cyclic peptides were isolated
in 58–64% yield. All the azido–alkyne acyclic peptides (9a–k)
and cyclic peptides (10a–k) were characterized by 1H-NMR, 13C-
NMR, FT-IR, ESI-MS and the purity of the compounds was
checked by HPLC. Remarkable differences were observed in the
NMR and IR spectra for the azido–alkyne acyclic peptides 9 and
the cyclic peptides 10; the alkyne proton peak for 9 was observed
at d 2.5 ppm by 1H-NMR whilst for 10 it had disappeared and a
new peak was observed at d 7.6 ppm from the triazole proton. A
sharp peak from the azide in 9 was observed at 2103 cmꢀ1 by FT-
IR which was not present in 10. In addition, the melting point
ꢂ
(mp) of 9a-k was around 100 C while the mp of cyclic peptide
10a-k was much higher i.e. around 250 ꢂC. Furthermore, in the
HPLC analysis 9 showed two different values for absorbance, at
244 nm and 215 nm for the azide and amide group respectively,
while for 10 a sharp peak appeared at 215 nm. The exact three
dimensional crystal structure of 10e was established by X-ray
diffraction (Fig. 2(a), ESI‡) and the crystal geometry was
compared with the optimized gas phase geometry (Fig. 2(b)),
highlighting the differences in molecular conformation (see
ESI†). Furthermore, COSY, DEPT, TOCSY and HSQC experi-
ments were also performed (see ESI†).
Scheme 2 Synthesis of CDPT ring 10a. Reagents and conditions: (i) Fig. 2 (a) ORTEP diagram of 10e drawn with 50% ellipsoidal proba-
Propargyl alcohol, CDI, THF, 0 ꢂC, 1 h, rt, 8 h, (ii) TFA, DCM, 0 ꢂC, 2 h, (iii) bility. The dotted line indicates the weak intramolecular C–H/O
BocNH–CH(CH2Ph)–COOH 5b, CDI, THF, 0 ꢂC, 1 h, rt, 8 h, (iv) Azido hydrogen bond. (b) Structure overlay of solid state geometry (C-atoms
propionic acid 8, EDC$HCl/HOBt, DCM, 0 ꢂC, 12 h, (v) Copper(I) are gray) of 10e with optimized geometry of the isolated molecule (C-
bromide, DBU, toluene, 110 ꢂC, 14 h.
atoms are purple) at MP2/6-311G**.
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In summary, we have demonstrated application of click
chemistry for the synthesis of a new class of cyclic depsipeptides
containing triazole rings. The methodology has been explored
for the synthesis of a library of CDPTs and structural evidence
was obtained from IR, ESI-MS, NMR, COSY, DEPT, TOCSY and
HSQC and X-ray crystallography. We also anticipate that the
proposed protocol can be useful for the synthesis of various
diverse cyclic peptides.
5 V. O. Rodionov, V. V. Fokin and M. G. Finn, Angew. Chem.,
Int. Ed., 2005, 44, 2210.
6 (a) K. D. Bodine, D. Y. Gin and M. S. Gin, J. Am. Chem. Soc.,
2004, 126, 1638; (b) M. Roice, I. Johannsen and M. Meldal,
QSAR Comb. Sci., 2004, 23, 662; (c) S. Punna, J. Kuzelka,
Q. Wang and M. G. Finn, Angew. Chem., Int. Ed., 2005, 44,
2215; (d) J. F. Billing and U. J. Nilsson, J. Org. Chem., 2005,
70, 4847; (e) J. H. Van Maarseveen, W. S. Horne and
M. R. Ghadiri, Org. Lett., 2005, 7, 4503; (f) Y. Angell and
K. Burgess, J. Org. Chem., 2005, 70, 9595.
7 G. L. Amidon and H. J. Lee, Annu. Rev. Pharmacol. Toxicol.,
1994, 34, 321.
8 V. D. Bock, R. Perciaccante, T. P. Jansen, H. Hiemstra and
J. H. V. Maarseveen, Org. Lett., 2006, 8, 919.
Notes and references
1 (a) J. Shoji, H. Hinoo, K. Matsumoto, T. Hattori, T. Yoshida,
S. Matsuura and E. Kondo, J. Antibiot., 1988, 41, 713; (b)
J. O'Sullivan, J. E. McCullough, A. A. Tymiak, D. R. Kirsch,
W. H. Trejo and P. A. Principe, J. Antibiot., 1988, 1740; (c)
D. Lacroix, S. Prado, D. Kamoga, J. Kasenene, S. Zirah and
B. Bodo, Org. Lett., 2012, 14, 576.
2 (a) F. Cavelier-Frontin, S. Achmad, J. Verducci, R. Jacquier
and G. Pepe, J. Mol. Struct.: THEOCHEM, 1993, 105, 125; (b)
F. Cavelier-Frontin, G. Pepe, J. Verducci, D. Siri and
R. Jacquier, J. Am. Chem. Soc., 1992, 114, 8885.
9 G. N. Belofsky, P. R. Jensen and W. Fenical, Tetrahedron Lett.,
1999, 40, 2913.
10 (a) C. L. Carroll, J. V. C. Johnston, A. Kekec, J. D. Brown,
E. Parry, J. Cajica, I. Medina, K. M. Cook, R. Corral,
P. S. Pan and S. R. McAlpine, Org. Lett., 2005, 7, 3481; (b)
R. A. Rodriguez, P. S. Pan, C. M. Pan, S. Ravula, S. Lapera,
E. K. Singh, T. J. Styers, J. D. Brown, J. Cajica, E. Parry,
K. Otrubova and S. R. McAlpine, J. Org. Chem., 2007, 72,
1980; (c) K. Otrubova, G. Lushington, D. V. Velde,
K. L. McGuire and S. R. McAlpine, J. Med. Chem., 2008, 51, 530.
3 (a) H. C. Kolb and K. B. Sharpless, Drug Discovery Today,
2003, 8, 1128; (b) W. S. Horne, C. D. Stout and
M. R. Ghadiri, J. Am. Chem. Soc., 2003, 125, 9372; (c)
W. S. Horne, M. K. Yadav, C. D. Stout and M. R. Ghadiri, J. 11 M. R. Davis, T. J. Styers, R. A. Rodrignez, P. S. Pan,
Am. Chem. Soc., 2004, 126, 15366; (d) A. Brik,
R. C. Vasko and S. McAlpine, Org. Lett., 2008, 10, 177.
J. Alexandratos, Y.-C. Lin, J. H. Elder, A. J. Olson, 12 (a) S. K. Agrawal, M. Sathe, A. K. Halve and M. P. Kaushik,
A. Wlodawer, D. S. Goodsell and C.-H. Wong,
ChemBioChem, 2005, 6, 1167.
4 (a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and
K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596; (b)
C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem.,
2002, 67, 3057; (c) For a recent review, see: V. D. Bock,
Tetrahedron Lett., 2012, 53, 5996; (b) P. Bandyopadhyay,
S. K. Agrawal, M. Sathe, P. Sharma and M. P. Kaushik,
Tetrahedron, 2012, 68, 3822; (c) M. Sathe, R. Ghorpade,
S. Merwyn, G. S. Agarwal and M. P. Kaushik, Analyst, 2012,
137, 406; (d) M. Sathe and M. P. Kaushik, Bioorg. Med.
Chem. Lett., 2010, 20, 1312.
H. Hiemstra and J. H. Van Maarseveen, Eur. J. Org. Chem., 13 N. T. Huynh, Y. S. Jeon, D. Kim and J. H. Kim, Polymer, 2013,
2006, 51.
54, 1341.
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